The present invention encompasses novel pyridazinone compounds useful in the treatment of cyclooxygenase-2 mediated diseases. More particularly, this invention concerns a method of inhibiting prostaglandin biosynthesis, particularly the induced prostaglandin endoperoxide H synthase (PGHS-2, cyclooxygenase-2, COX-2) protein.
The prostaglandins are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The discovery of two forms of prostaglandin endoperoxide H synthase, isoenzymes PGHS-1 and PGHS-2, that catalyze the oxidation of arachidonic acid leading to prostaglandin biosynthesis has resulted in renewed research to delineate the role of these two isozymes in physiology and pathophysiology. These isozymes have been shown to have different gene regulation and represent distinctly different prostaglandin biosynthesis pathways. The PGHS-1 pathway is expressed constitutively in most cell types. It responds to produce prostaglandins that regulate acute events in vascular homeostasis and also has a role in maintaining normal stomach and renal function. The PGHS-2 pathway involves an induction mechanism which has been linked to inflammation, mitogenesis and ovulation phenomena.
Prostaglandin inhibitors provide therapy for pain, fever, and inflammation, and are useful therapies, for example in the treatment of rheumatoid arthritis and osteoarthritis. The non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and fenamates inhibit both isozymes. Inhibition of the constitutive enzyme PGHS-1 results in gastrointestinal side effects including ulcers and bleeding and incidence of renal problems with chronic therapy. Inhibitors of the induced isozyme PGHS-2 may provide anti-inflammatory activity without the side effects of PGHS-1 inhibitors.
The problem of side-effects associated with NSAID administration has never completely been solved in the past. Enteric coated tablets and co-administration with misoprostol, a prostaglandin derivative, have been tried in an attempt to minimize stomach toxicity. It would be advantageous to provide compounds which are selective inhibitors of the induced isozyme PGHS-2.
The present invention discloses novel compounds which are selective inhibitors of PGHS-2.
The present invention discloses pyridazinone compounds which are selective inhibitors of cyclooxygenase-2 (COX-2). The the compounds of the present invention have the formula I: 
where
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy), xe2x80x94C(O)R5, xe2x80x94(CH2)nC(O)R5, xe2x80x94R6xe2x80x94R7, xe2x80x94(CH2)nCH(OH)R5, xe2x80x94(CH2)nCH(ORd)R5, xe2x80x94(CH2)nC(NORd)R5, xe2x80x94(CH2)nC(NRd)R5, xe2x80x94(CH2)nCH(NORd)R5, xe2x80x94(CH2)nCH(NRdRe)R5, xe2x80x94(CH2)nCxe2x89xa1Cxe2x80x94R7, xe2x80x94(CH2)n[CH(CXxe2x80x23)]mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n(C Xxe2x80x22)mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n[CH(CXxe2x80x23)]mxe2x80x94(CH2)nxe2x80x94R8, xe2x80x94(CH2)n(C Xxe2x80x22)mxe2x80x94(CH2)nR8, xe2x80x94(CH2)n(CHXxe2x80x2)mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n(CHXxe2x80x2)mxe2x80x94(CH2)nxe2x80x94R8, and xe2x80x94(CH2)nxe2x80x94R20,
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic (alkyl);
wherein R6 is alkylene or alkenylene;
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
Xxe2x80x2 is halogen;
n is from 0 to about 10, and m is 0 to about 5; at least one of R1, R2 and R3 is a group, substituted with a substituent having a group xe2x80x94X1xe2x80x94R9, having the formula: 
where X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, xe2x80x94SO(NR10)xe2x80x94, xe2x80x94PO(OR11)xe2x80x94, and xe2x80x94PO(NR12R13)xe2x80x94,
R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, xe2x80x94NHNH2, alkylamino, dialkylamino, alkoxy, thiol, alkylthiol, and protecting groups,
X2 is selected from the group consisting of hydrogen or halogen;
R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R12 and R13 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.
The remaining two of the groups of R1, R2, and R3, are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro, and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(R16) (R17)xe2x80x94,
C(O)NR21xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NC(O)xe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; and
R21 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The present invention discloses pyridazinone compounds which are cyclooxygenase (COX) inhibitors and are selective inhibitors of cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important xe2x80x9chousekeepingxe2x80x9d enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys.
In one embodiment, the compounds of the present invention have the formula I: 
where
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy), xe2x80x94C(O)R5, xe2x80x94(CH2)nC(O)R5, xe2x80x94R6xe2x80x94R7, xe2x80x94(CH2)nCH(OH)R5, xe2x80x94(CH2)nCH(ORd)R5, xe2x80x94(CH2)nC(NORd)R5, xe2x80x94(CH2)nC(NRd)R5, xe2x80x94(CH2)nCH(NORd)R5, xe2x80x94(CH2)nCH(NRdRe)R5, xe2x80x94(CH2)nCxe2x89xa1Cxe2x80x94R7, xe2x80x94(CH2)n[CH(CXxe2x80x23)]mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n(C Xxe2x80x22)mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n[CH(CXxe2x80x23)]mxe2x80x94(CH2)nxe2x80x94R8, xe2x80x94(CH2)n(C Xxe2x80x22)mxe2x80x94(CH2)nR8, xe2x80x94(CH2)n(CHXxe2x80x2)mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n(CHXxe2x80x2)mxe2x80x94(CH2)nxe2x80x94R8, and xe2x80x94(CH2)nxe2x80x94R20,
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic (alkyl);
wherein R6 is alkylene or alkenylene;
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);
Xxe2x80x2 is halogen;
n is from 0 to about 10, and m is 0 to about 5; at least one of R1, R2 and R3 is a group, substituted with a substituent having a group xe2x80x94X1xe2x80x94R9, having the formula: 
where X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, xe2x80x94SO(NR10)xe2x80x94, xe2x80x94PO(OR11)xe2x80x94, and xe2x80x94PO(NR12R13)xe2x80x94,
R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, xe2x80x94NHNH2, alkylamino, dialkylamino, alkoxy, thiol, alkylthiol, and protecting groups,
X2 is selected from the group consisting of hydrogen or halogen;
R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R12 and R13 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.
The remaining two of the groups of R1, R2, and R3, are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro, and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(R16) (R17)xe2x80x94,
C(O)NR21xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NC(O)xe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; and
R21 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another embodiment, compounds of the present invention have the formula II: 
wherein Z is a group having the formula: 
where X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, -and SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino;
X2is selected from the group consisting of hydrogen or halogen;
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, hetrocyclic (alkyl), and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy), xe2x80x94C(O)R5, xe2x80x94(CH2)nC(O)R5, xe2x80x94(CH2)nCxe2x89xa1Cxe2x80x94R7, xe2x80x94(CH2)n[CH(CXxe2x80x23)]mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(C H2)n(C Xxe2x80x22)mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n[CH(CXxe2x80x23)]mxe2x80x94(CH2)nxe2x80x94R8, xe2x80x94(CH2)n(C Xxe2x80x22)mxe2x80x94(CH2)nR8, xe2x80x94(CH2)n(CHXxe2x80x2)mxe2x80x94(CH2)nxe2x80x94CXxe2x80x23, xe2x80x94(CH2)n(CHXxe2x80x2)mxe2x80x94(CH2)nxe2x80x94R8, and xe2x80x94(CH2)nxe2x80x94R20,
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl),
R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
Xxe2x80x2 is halogen;
n is from 0 to about 10, m is from 0 to about 5;
R1and R2 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, hetreocyclic (alkyl), cyano, nitro, and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94C(R16)(R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and
R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, hetrocyclic, heterocyclic (alkyl), or cyano;; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In yet another embodiment, compounds of the present invention have the formula III: 
wherein X, X1, R, R1, R3, and R9 are as defined in Formula I; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In a preferred embodiment, compounds of the present invention have the formula III, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, xe2x80x94(CH2)nC(O)R5, xe2x80x94(CH2)nCxe2x89xa1Cxe2x80x94R7, xe2x80x94(CH2)n(CXxe2x80x22)mCXxe2x80x23, xe2x80x94(CH2)n(CXxe2x80x2Re)mCXxe2x80x23, xe2x80x94(CH2)n(CXxe2x80x22)mR8, xe2x80x94(CH2)n(CH2)n(CXxe2x80x2Re)mR8, and xe2x80x94(CH2)nxe2x80x94R20;
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl), R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
Xxe2x80x2 is halogen;
Re is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxy, and haloalkyl;
n is from 0 to about 10, m is from 0 to about 5;
R1 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16)(R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, xe2x80x94(CH2)nC(O)R5, and xe2x80x94(CH2)nxe2x80x94R20;
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);
R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
n is from 0 to about 10;
R1 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16)(R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, and xe2x80x94(CH2)nC(O)R5,;
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl); and
n is from 0 to about 10;
R1 and R3 are independently selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16)(R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and Ra, Rb, and Rc. are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;
R is selected from hydrogen, haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and xe2x80x94(CH2)nxe2x80x94R20 where is R20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;
n is from 0 to about 10;
R1 and R3 are independently selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16) (R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and Ra, Rb, and Rc. are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;
R is selected from hydrogen, haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and xe2x80x94(CH2)nxe2x80x94R20 where is R20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;
n is from 0 to about 10;
R1 and R3 are independently selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl); or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X is selected from the group consisting of O, S, NR4, Nxe2x80x94ORa, and Nxe2x80x94NRbRc, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;
R is selected from hydrogen, haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and xe2x80x94(CH2)nxe2x80x94R20 where is R20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;
n is from 0 to about 10;
R1 and R3 are independently selected from the group consisting of hydrogen, phenyl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine including, but not limited to, p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, and the like; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In yet another embodiment, compounds of the present invention have formula IV: 
where R, R1, X1, X2, R9, and R3 are as described in Formula I; or a pharmaceutically acceptable salt or ester thereof.
In a preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, xe2x80x94(CH2)nC(O)R5, xe2x80x94(CH2)nCxe2x89xa1Cxe2x80x94R7, xe2x80x94(CH2)n(CXxe2x80x22)mCXxe2x80x23, xe2x80x94(CH2)n(CXxe2x80x2Re)mCXxe2x80x23, xe2x80x94(CH2)n(CXxe2x80x22)mR8, xe2x80x94(CH2)n(CXxe2x80x2Re)mR8, and xe2x80x94(CH2)nxe2x80x94R20;
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl), R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
Xxe2x80x2 is halogen;
Re is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxy, and haloalkyl;
n is from 0 to about 10, m is from 0 to about 5;
R1 is hydrogen and R3 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16) (R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, xe2x80x94(CH2)nC(O)R5 and xe2x80x94(CH2)nxe2x80x94R20;
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);
R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);
n is from 0 to about 10;
R1 is hydrogen and R3 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16) (R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, and xe2x80x94(CH2)nC(O)R5;
wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl); and
n is from 0 to about 10;
R1 is hydrogen and R3 is selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16) (R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is selected from hydrogen, haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and xe2x80x94(CH2)nxe2x80x94R20 where is R20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;
n is from 0 to about 10;
R1 is hydrogen and R3 is selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and xe2x80x94Yxe2x80x94R14, wherein Y is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHR15xe2x80x94, xe2x80x94C(R16) (R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR19xe2x80x94. R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and
R15, R16, R17, and R19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is selected from hydrogen, haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and xe2x80x94(CH2)nxe2x80x94R20 where is R20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;
n is from 0 to about 10;
R1 is hydrogen and R3 is selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl); or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is selected from hydrogen, haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and xe2x80x94(CH2)nxe2x80x94R20 where is R20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;
n is from 0 to about 10;
R1 is hydrogen and R3 is selected from the group consisting of hydrogen, phenyl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine including, but not limited to, p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, and the like; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is haloalkyl, R1 is hydrogen and R3 is selected from the group consisting of hydrogen and phenyl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein X1 is selected from the group consisting of xe2x80x94SO2xe2x80x94, and xe2x80x94SO(NR10)xe2x80x94, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
R is substituted and unsubstituted aryl and R1 is hydrogen and R3 is selected from the group consisting of hydrogen and phenyl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula IV, wherein Xxe2x80x2 is SO2, R9 is selected from alkyl and amino, R is substituted and unsubstituted aryl and R1 is hydrogen and R3 is selected from the group consisting of hydrogen and phenyl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
Preferred Embodiments
Compounds useful in practicing the present invention include, but are not limited to:
5-(4-Methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-Benzyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-Methyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-Ethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(4-Fluorobenzyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(n-Butyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(2,2,2-Trifluroethyl)-5-(4-methylsulfonylphenyl)-6-(4-flurophenyl)-3(2H)-pyridazinone;
2-(4-Fluoro-xcex1-methylbenzyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(n-Propyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2 H)-pyridazinone;
2-(n-Pentyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2 H)-pyridazinone;
2-Cyclohexylmethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2 H)-pyridazinone;
2-Phenacyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2 H)-pyridazinone;
2-Propargyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-Cyclohexyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(2-Butynyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;
2-(Cyclobutanylmethyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone; and
2-(3-Methylbuten-2-yl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
Preparation of Compounds of the Invention
The compounds of the invention may be prepared by a variety of synthetic routes. Representative procedures are outlined in Scheme 1 below. A general route to the compounds of the invention having Formula III, where the aryl group at the 5-position on the pyridazinone ring is substituted with a sulfonyl group ring (R2 is aminosulfonyl, or methylsulfonyl, shown as methylsulfonyl) is described in Scheme 1, below. Phenyl acetic acid, optionally substituted, was condensed with a benzaldehyde to form the corresponding 2-phenyl-trans-cinnamic acid. The trans-cinnamic acid was converted to the corresponding acid chloride which was then decarbonylated to provide the benzyl-aryl ketone. The ketone was then alkylated with ethyl bromoacetate in the presence of a strong base such as sodium bis(trimethylsilyl)amide. Treatment of the ketoester product with hydrazine, in an alcohol solvent, such as ethanol, provided dihydropyridazinone. The dihydropyridazinone was dehydrogenated to form the pyridazinone by treatment with Bromine in acetic acid. If desired, the Rxe2x80x2 group can be added via substitution using an appropriate alkylating agent. In Scheme 1, X is defined as in R3 and Rxe2x80x2 is defined as in R. 
Definitions of Terms
As used throughout this specification and the appended claims, the following terms have the meanings specified.
The term xe2x80x9cprotecting groups includes xe2x80x9ccarboxy protecting groupxe2x80x9d and xe2x80x9cN-protecting groupsxe2x80x9d. xe2x80x9cCarboxy protecting groupxe2x80x9d as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in xe2x80x9cPro-drugs as Novel Delivery Systemsxe2x80x9d, Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of xe2x80x9cBioreversible Carriers in Drug Design: Theory and Applicationxe2x80x9d, edited by E. B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C1 to C8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl, 1-methyl-1-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (John Wiley and Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (t-Boc) and benzyloxycarbonyl (Cbz).
The term xe2x80x9calkanoylxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (xe2x80x94C(O)xe2x80x94) group. Examples of alkanoyl include acetyl, propionyl and the like.
The term xe2x80x9calkanoylaminoxe2x80x9d as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
The term xe2x80x9calkenylenexe2x80x9d denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2CHxe2x95x90CHCH2xe2x80x94, and the like.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (xe2x80x94Oxe2x80x94) linkage. Examples of alkenyloxy include allyloxy, butenyloxy and the like.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to R41Oxe2x80x94 wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to R80Oxe2x80x94R81Oxe2x80x94 wherein R80 is loweralkyl as defined above and R81 is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term xe2x80x9calkoxyalkoxyalkenylxe2x80x9d as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkenyl radical. Representative examples of alkoxyalkoxyalkenyl groups include methoxyethoxyethenyl, methoxymethoxymethenyl, and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkoxy group as previously defined appended to an alkylene as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
The term xe2x80x9c(alkoxycarbonyl)thioalkoxyxe2x80x9d as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical. Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The terms xe2x80x9calkylxe2x80x9d and xe2x80x9cloweralkylxe2x80x9d as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to R51NHxe2x80x94 wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term xe2x80x9calkylcarbonylalkylxe2x80x9d as used herein refers to R40xe2x80x94C(O)xe2x80x94R41xe2x80x94 wherein R40 is an alkyl group and R41 is alkylene.
The term xe2x80x9calkylenexe2x80x9d denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2C(CH3)2CH2xe2x80x94 and the like.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonyl (xe2x80x94S(O)2xe2x80x94) group. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.
The term xe2x80x9calkylsulfonylalkylxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylalkyl (xe2x80x94S(O)2xe2x80x94R52xe2x80x94) group wherein R52 is alkylene. Examples of alkylsulfonylalkyl include methylsulfonylmethyl (CH3xe2x80x94S(O)2xe2x80x94CH2xe2x80x94), ethylsulfonylmethyl, isopropylsulfonylethyl and the like.
The term xe2x80x9calkylsulfonylaminoxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (xe2x80x94S(O)2xe2x80x94NHxe2x80x94) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
The term xe2x80x9calkylsulfonylarylalkylxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylalkyl (xe2x80x94S(O)2xe2x80x94R45R33xe2x80x94) group wherein R45 is aryl and R33 is alkylene. Examples of alkylsulfonylarylalkyl include methylsulfonylphenylmethyl ethylsulfonylphenylmethyl, isopropylsulfonylphenylethyl and the like.
The term xe2x80x9calkylthioxe2x80x9d as used herein refers to R53Sxe2x80x94 wherein R53 is alkyl.
The term xe2x80x9calkynylxe2x80x9d as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94H, Hxe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, Hxe2x80x94Cxe2x89xa1Cxe2x80x94CH(CH3)xe2x80x94 and the like.
The term xe2x80x9camidoxe2x80x9d as used herein refers to R54xe2x80x94C(O)xe2x80x94NHxe2x80x94 wherein R54 is an alkyl group.
The term xe2x80x9camidoalkylxe2x80x9d as used herein refers to R34xe2x80x94C(O)xe2x80x94NHR35xe2x80x94 wherein R34 is alkyl and R35 is alkylene.
The term xe2x80x9caminoxe2x80x9d as used herein refers xe2x80x94NH2.
The term xe2x80x9caminocarbonylxe2x80x9d as used herein refers to H2Nxe2x80x94C(O)xe2x80x94.
The term xe2x80x9caminocarbonylalkyl xe2x80x9d as used herein refers to an aminocarbonyl as described above appended to the parent molecular moiety through an alkylene.
The term xe2x80x9caminocarbonylalkoxyxe2x80x9d as used herein refers to H2Nxe2x80x94C(O)xe2x80x94Oxe2x80x94R55xe2x80x94, wherein R55 is an alkyl radical group. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (xe2x95x90O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, alkylimino (R*Nxe2x95x90 wherein R* is a loweralkyl group), amino, alkylamino, alkylsulfonyl, dialkylamino, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, aryl, arylalkyl, arylalkoxy, aryloxy, mercapto, cyano, nitro, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, xe2x80x94SO3H, hydroxalkoxy, phenyl and tetrazolylalkoxy. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like.
The term xe2x80x9carylalkenylxe2x80x9d as used herein refers to an alkenylene to which is appended an aryl group, for example, phenylethenyl and the like.
The term xe2x80x9carylalkynylxe2x80x9d as used herein refers to an alkynyl radical to which is appended an aryl group, for example, phenylethynyl and the like The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to R42Oxe2x80x94 wherein R42 is an arylalkyl group, for example, benzyloxy, and the like.
The term xe2x80x9carylalkylxe2x80x9d as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term xe2x80x9carylalkylaminoxe2x80x9d as used herein refers to an arylalkyl group as previously defined, appended to the parent molecular moiety through an amino group.
The term xe2x80x9carylaminoxe2x80x9d as used herein refers to R45NH2xe2x80x94 wherein R45 is an aryl.
The term xe2x80x9carylcarbonylalkylxe2x80x9d as used herein refers to R45C(O)R33xe2x80x94 wherein R45 is an aryl group and R33 is an alkylene group.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to R45Oxe2x80x94 wherein R45 is an aryl group, for example, phenoxy, and the like.
The term xe2x80x9ccarboxaldehydexe2x80x9d as used herein refers to a formaldehyde radical, xe2x80x94C(O)H.
The term xe2x80x9ccarboxamidexe2x80x9d as used herein refers to xe2x80x94C(O)NH2.
The term xe2x80x9ccarboxyxe2x80x9d as used herein refers to a carboxylic acid radical, xe2x80x94C(O)OH.
The term xe2x80x9ccarboxyalkenylxe2x80x9d as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-1-ethenyl and the like.
The term xe2x80x9ccarboxyalkylxe2x80x9d as used herein refers to a carboxy group as previously defined appended to an alkyl radical as previously defined. Examples of carboxyalkyl include 2-carboxyethyl, 3-carboxy-1-propyl and the like.
The term xe2x80x9ccarboxyalkoxyxe2x80x9d as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.
The term xe2x80x9ccyanoxe2x80x9d as used herein refers a cyano (xe2x80x94CN) group.
The term xe2x80x9ccyanoalkyxe2x80x9d as used herein refers to a cyano (xe2x80x94CN) group appended to the parent molecular moiety through an alkyl. Examples of cyanoalkyl include 3-cyanopropyl, 4-cyanobutyl, and the like.
The term xe2x80x9ccyanoalkoxyxe2x80x9d as used herein refers to a cyano (xe2x80x94CN) group appended to the parent molecular moiety through an alkoxy radical. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from hydroxy, halo, oxo (xe2x95x90O), alkylimino (R*Nxe2x95x90 wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, xe2x80x94SO3H, nitro, cyano and loweralkyl.
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings containing at least one double bond in the ring structure. Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, oxo (xe2x95x90O), alkylimino (R*Nxe2x95x90 wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl , xe2x80x94SO3H, nitro, cyano and loweralkyl.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
The term xe2x80x9ccycloalkenylalkylxe2x80x9d as used herein refers to a cycloalkenyl group appended to a loweralkyl radical, including but not limited to cyclohexenylmethyl.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to (R56)(R57)N- wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
The term xe2x80x9cdiarylaminoxe2x80x9d as used herein refers to (R45)(R46)N- wherein R45 and R46 are independently aryl, for example diphenylamino and the like.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to I, Br, Cl or F.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to an alkyl radical, as defined above, which has at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl, 2,3-difluropentyl, and the like.
The term xe2x80x9chaloalkenylxe2x80x9d as used herein refers to an alkenyl radical has at least one halogen substituent.
The term xe2x80x9chaloalkynylxe2x80x9d as used herein refers to an alkynyl radical has at least one halogen substituent.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. Examples of heterocycles include, but are not limited to, thiophene, pyrrole, and furan. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cycloalkane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl pyrimidyl and benzothienyl. Heterocyclics also include compounds of the formula 
where X* is xe2x80x94CH2xe2x80x94 or xe2x80x94Oxe2x80x94 and Y* is xe2x80x94C(O)xe2x80x94 or [xe2x80x94C(Rxe2x80x3)2xe2x80x94]v where Rxe2x80x3 is hydrogen or C1-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or be substituted with one, two , or three substituents independently selected from hydroxy, halo, oxo (xe2x95x90O), alkylimino (R*Nxe2x95x90 wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, xe2x80x94SO3H, nitro, cyano and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.
The term xe2x80x9cheterocyclic(alkoxy)xe2x80x9d as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of (heterocyclic)alkoxy include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
The term xe2x80x9cheterocyclic(alkyl)xe2x80x9d as used herein refers to a heterocyclic group as defined above appended to the parent molecular moiety through a loweralkyl radical as defined above.
The term xe2x80x9cheterocyclic(oxy)xe2x80x9d as used herein refers to a heterocyclic group as defined above appended to the parent molecular moiety through an oxygen. Examples of (heterocyclic)oxy include 4-pyridyloxy, 2-pyridyloxy and the like.
The term xe2x80x9chydroxyxe2x80x9d as used herein refers to xe2x80x94OH.
The term xe2x80x9chydroxyalkoxyxe2x80x9d as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (xe2x80x94OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a hydroxy group.
The term xe2x80x9cmercaptoxe2x80x9d or xe2x80x9cthiolxe2x80x9d as used herein refers to xe2x80x94SH.
The term xe2x80x9cnitroxe2x80x9d as used herein refers to xe2x80x94NO2.
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to R70Sxe2x80x94 wherein R70 is alkoxy. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting a carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d as used herein refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
The term xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to provide the parent compound having the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
As used throughout this specification and the appended claims, the term metabolically cleavable group denotes a moiety which is readily cleaved in vivo from the compound bearing it, wherein said compound, after cleavage remains or becomes pharmacologically active. Metabolically cleavable groups form a class of groups reactive with the carboxyl group of the compounds of this invention are well known to practitioners of the art. They include, but are not limited to groups such as, for example, alkanoyl, such as acetyl, propionyl, butyryl, and the like; unsubstituted and substituted aroyl, such as benzoyl and substituted benzoyl; alkoxycarbonyl, such as ethoxycarbonyl; trialkylsilyl, such as trimethyl- and triethysilyl; monoesters formed with dicarboxylic acids, such as succinyl, and the like. Because of the ease with which the metabolically cleavable groups of the compounds of this invention are cleaved in vivo, the compounds bearing such groups act as pro-drugs of other prostaglandin biosynthesis inhibitors. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group.
Asymmetric centers may exist in the compounds of the present invention. The present invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds of the present invention are made by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation as, for example, by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques, or by direct separation of the optical enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the organic chemical arts.
The following examples illustrate the process of the invention, without limitation.